The accident happened at about 2:30 on Saturday afternoon near the intersection of Yonge and Gerrard streets.
The motorcycle may have hit a cyclist before mounting the sidewalk where it struck some pedestrians.
One witness told CBC News that bystanders rushed to help the man who was gravely injured, but didn't appear to be successful.
"A couple of people tried to give him CPR" said Paul Marqus, "but he never came to."
Three injured were taken to hospital, according to police.
The area has been closed off while police conduct their investigation.
It is not clear if the victim was a pedestrian or the motorcyclist.
Police have released any names.